Clinically useful antagonists exist for estrogens, androgens, and mineralocorticoids. Antagonists for the glucocorticoids or the progestins with potential clinical usefulness have been discovered only recently. The objective of this project is to develop and study the molecular mechanisms of action and the human applications of the antagonists for both of these classes of steroids. Initially, we proved that glucocorticoid antagonists can be developed by modifications of the 11-position of the steroidal C ring of glucocorticoids. Then we tested a prototype glucocorticoid-progestin antagonist (RU 486) developed recently by Roussel-UCLAF. This compound has strong affinities for the human glucocorticoid and progestin receptor and is devoid of agonist effects in small experimental animals. Given to nonhuman primates or man RU 486 causes prolonged elevations of plasma ACTH, cortisol and arginine vasopressin, all changes preventable by previous administration of a glucocorticoid (dexamethasone). This suggests that antiglucocorticoids could be used for challenging the hypothalamic-pituitary-adrenal axis when clinical testing is required in patients with disorders of this axis. Antiglucocorticoid therapy of patients with severe Cushing's syndrome due to ectopic ACTH secretion or adrenocortical tumors causes remission of the clinical manifestations of hypercortisolism. We have treated 7 patients and are currently enlarging the therapy series, including patients with Cushing's syndrome prepared for major surgery. Given to women in single monthly doses during the luteal phase of the cycle RU 486 causes vaginal bleeding. The subsequent cycle is of normal duration. This suggests that single doses of RU 486 could be used for contraception.